Fas-deficient lpr mice are more susceptible to graft-versus-host disease

The Fas/Fas ligand (FasL) pathway is involved in a variety of regulatory me chanisms that could be important for the development of graft-vs-host disea se (GVHD) after bone marrow transplantation (BR IT), such as cytolysis of t arget cells by cytotoxic T cells, regulation of inflammatory responses, per ipheral deletion of autoimmune cells, costimulation of T cells, and activat ion-induced cell death. To further evaluate the role of Fas/FasL in the com plex pathophysiology of GVHD, we used Fas-deficient B6.lpr mice as recipien ts in a MHC-matched minor histocompatibility Ag-mismatched murine model for GVHD after allogeneic BMT (C3H.SW --> B6), We found a significantly higher morbidity and mortality from GVHD compared with control B6 recipients. In contrast, B6.lpr recipients had very little hepatic GVHD, although all othe r specific GVHD target organs (skin, intestines, and thymus) were more seve rely affected than in the control B6 recipients. B6,lpr recipients with GVH D demonstrated intact donor lymphoid engraftment and an increase in expansi on of donor T cells and monocytes/macrophages compared with control B6 reci pients. Serum levels of IFN-gamma and TNF-alpha were higher in B6,lpr recip ients than in control B6 recipients, and monocytes/macrophages in B6.lpr re cipients appeared more sensitized. B6,lpr recipients had more residual peri toneal macrophages after BMT, and peritoneal macrophages from B6.lpr mice c ould induce a greater proliferative response from C3H.SW splenocytes, This study demonstrates that the expression of Fas in the recipient is required for GVHD of the liver, but show's unexpected consequences when host tissues lack the expression of Fas for the development of GVHD in other organs and systemic GVHD.